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Biomedical subjects

Igor R Efimov

Publications and source records attributed to Igor R Efimov.

At least 19 recordsLinked to original sources
PubMed2006

Localization of Na+ channel isoforms at the atrioventricular junction and atrioventricular node in the rat.

BACKGROUND: The electrical activity of the atrioventricular node (AVN) is functionally heterogeneous, but how this relates to distinct cell types and the 3-dimensional structure of the AVN is unknown. To address this, we have studied the expression of Na(V)1.5 and other Na+ channel isoforms in the AVN. METHODS AND RESULTS: The rat AVN was identified by Masson's trichrome staining together with immunolabeling of marker proteins: connexin40, connexin43, desmoplakin, atrial natriuretic peptide, and hyperpolarization-activated and cyclic nucleotide-gated channel 4. Na+ channel expression was investigated with immunohistochemistry with isoform-specific Na+ channel antibodies. Na(V)1.1 was distributed in a similar manner to Na(V)1.5. Na(V)1.2 was not detected. Na(V)1.3 labeling was present in nerve fibers and cell bodies (but not myocytes) and was abundant in the penetrating atrioventricular (AV) bundle and the common bundle but was much less abundant in other regions. Na(V)1.5 labeling was abundant in the atrial and ventricular myocardium and the left bundle branch. Na(V)1.5 labeling was absent in the open node, penetrating AV bundle, AV ring bundle, and common bundle but present at a reduced level in the inferior nodal extension and transitional zone. Na(V)1.6 was not detected. CONCLUSIONS: Our findings provide molecular evidence of multiple electrophysiological cell types at the AV junction. Impaired AV conduction as a result of mutations in or loss of Na(V)1.5 must be the result of impaired conduction in the AVN inputs (inferior nodal extension and transitional zone) or output (bundle branches) rather than the AVN itself (open node and penetrating AV bundle).

Animals↗
PubMed2006

Postganglionic nerve stimulation induces temporal inhibition of excitability in rabbit sinoatrial node.

Vagal stimulation results in complex changes of pacemaker excitability in the sinoatrial node (SAN). To investigate the vagal effects in the rabbit SAN, we used optical mapping, which is the only technology that allows resolving simultaneous changes in the activation pattern and action potentials morphologies. With the use of immunolabeling, we identified the SAN as a neurofilament 160-positive but connexin 43-negative region (n = 5). Normal excitation originated in the SAN center with a cycle length (CL) of 405 +/- 14 ms (n = 14), spread anisotropically along the crista terminalis (CT), and failed to conduct toward the septum. Postganglionic nerve stimulation (PNS, 400-800 ms) reduced CL by 74 +/- 7% transiently and shifted the leading pacemaker inferiorly (78%) or superiorly (22%) from the SAN center by 2-10 mm. In the intercaval region between the SAN center and the septal block zone, PNS produced an 8 +/- 1-mm(2) region of transient hyperpolarization and inexcitability. The first spontaneous or paced excitation following PNS could not enter this region for 500-1,500 ms. Immunolabeling revealed that the PNS-induced inexcitable region is located between the SAN center and the block zone and has a 2.5-fold higher density of choline acetyltransferase than CT but is threefold lower than the SAN center. The fact that the inexcitability region does not coincide with the most innervated area indicates that the properties of the myocytes themselves, as well as intercellular coupling, must play a role in the inexcitability induction. Optically mapping revealed that PNS resulted in transient loss of pacemaker cell excitability and unidirectional entrance conduction block in the periphery of SAN.

Actinin↗
PubMed2006

Mechanisms of unpinning and termination of ventricular tachycardia.

High-energy defibrillation shock is the only therapy for ventricular tachyarrhythmias. However, because of adverse side effects, lowering defibrillation energy is desirable. We investigated mechanisms of unpinning, destabilization, and termination of ventricular tachycardia (VT) by low-energy shocks in isolated rabbit right ventricular preparations (n = 22). Stable VT was initiated with burst pacing and was optically mapped. Monophasic "unpinning" shocks (10 ms) of different strengths were applied at various phases throughout the reentry cycle. In 8 of 22 preparations, antitachycardia pacing (ATP: 8-20 pulses, 50-105% of period, 0.8-10 mA) was also applied. Termination of reentry by ATP was achieved in only 5 of 8 preparations. Termination by unpinning occurred in all 22 preparations. Rayleigh's test showed a statistically significant unpinning phase window, during which reentry could be unpinned and subsequently terminated with E80 (magnitude at which 80% of reentries were unpinned) = 1.2 V/cm. All reentries were unpinned with field strengths < or = 2.4 V/cm. Unpinning was achieved by inducing virtual electrode polarization and secondary sources of excitation at the core of reentry. Optical mapping revealed the mechanisms of phase-dependent unpinning of reentry. These results suggest that a 20-fold reduction in energy could be achieved compared with conventional high-energy defibrillation and that the unpinning method may be more effective than ATP for terminating stable, pinned reentry in this experimental model.

Action Potentials↗
PubMed2006

Three-dimensional anatomy of the conduction system of the early embryonic rabbit heart.

The complete embryonic cardiac conduction system is difficult to view in three dimensions, primarily because there has not been a marker of all segments of the normal system throughout all stages of development. Imaging of the conduction system components within the atria has been particularly controversial because different markers reveal different pathways that may or may not represent conduction system components. The conduction system of the adult and embryonic rabbit, however, can be labeled in its entirety with the neurofilament marker, NF-160. The conduction system of rabbit embryos at several stages of development spanning cardiac septation was therefore investigated. Optical mapping of the electrical signature of the conduction system previously revealed a close correlation between the cardiac activation patterns and the anatomy as shown by serial sections. The 3D relationship between the components of the conduction system could only be inferred from the 2D sections. The sections were consequently reconstructed using a commercial software program (AutoQuant). This is the first demonstration of the three-dimensional complete normal rabbit embryonic cardiac conduction system at several stages of development.

Animals↗
PubMed2006

Present understanding of shock polarity for internal defibrillation: the obvious and non-obvious clinical implications.

BACKGROUND: Uncertainty about the best electrode configuration has combined with the programming flexibility in modern implantable cardioverter-defibrillators (ICDs) to result in routine polarity reversal during an implant to deal with a high defibrillation threshold (DFT). We feel that this practice is not always supported by the clinical data and the present scientific understanding of defibrillation. METHOD: A meta-analysis of the clinical studies on ICD shock polarity was performed. Subgroup analyses were also performed to test the impact of high DFTs, various tilts, and the use of the hot can electrode. A review of the basic research surrounding the effects of polarity in defibrillation is also presented. RESULTS: A total of 224 patients were studied. The use of an anodal right ventricular (RV) coil lowers the mean DFT by 14.8% (P = 0.00001). It provides thresholds equal to or lower than cathodal defibrillation in 83% of patients. The fraction of patients with lower anodal DFTs was 94/224 versus 38/224 for cathodal polarity. This phenomenon may be explained by virtual electrode effects. In particular, anodal electrodes tend to produce collapsing wavefronts while cathodal electrodes tend to produce expanding proarrhythmic wavefronts. CONCLUSION: In an ICD implant, the RV coil should be the anode. Furthermore, DFT testing beginning with cathodal defibrillation is most likely unnecessary and needlessly extends the procedure's duration and increases the risks for the patient.

Clinical Trials as Topic↗
PubMed2005

Differences between left and right ventricular chamber geometry affect cardiac vulnerability to electric shocks.

Although effects of shock strength and waveform on cardiac vulnerability to electric shocks have been extensively documented, the contribution of ventricular anatomy to shock-induced polarization and postshock propagation and thus, to shock outcome, has never been quantified; this is caused by lack of experimental methodology capable of mapping 3-D electrical activity. The goal of this study was to use optical imaging experiments and 3-D bidomain simulations to investigate the role of structural differences between left and right ventricles in vulnerability to electric shocks in rabbit hearts. The ventricles were paced apically, and uniform-field, truncated-exponential, monophasic shocks of reversed polarity were applied over a range of coupling intervals (CIs) in experiment and model. Experiments and simulations revealed that reversing the direction of externally-applied field (RV- or LV- shocks) alters the shape of the vulnerability area (VA), the 2-D grid encompassing episodes of arrhythmia induction. For RV- shocks, VA was nearly rectangular indicating little dependence of postshock arrhythmogenesis on CI. For LV- shocks, the probability of arrhythmia induction was higher for longer than for shorter CIs. The 3-D simulations demonstrated that these effects stem from the fact that reversal of field direction results in relocation of the main postshock excitable area from LV wall (RV- shocks) to septum (LV- shocks). Furthermore, the effect of septal (but not LV) excitable area in postshock propagation was found to strongly depend on preshock state. Knowledge regarding the location of the main postshock excitable area within the 3-D ventricular volume could be important for improving defibrillation efficacy.

Animals↗
PubMed2005

Mechanisms of enhanced shock-induced arrhythmogenesis in the rabbit heart with healed myocardial infarction.

Shock-induced vulnerability and defibrillation have been mostly studied in structurally normal hearts. However, defibrillation therapy is normally applied to patients with diseased hearts, frequently those with prior myocardial infarction (MI). Shock-induced vulnerability and defibrillation have not been well studied under this condition. We sought to examine the mechanisms of shock-induced arrhythmogenesis and arrhythmia maintenance in a rabbit model of healed MI (4 wk or more postinfarction). Ligation of the lateral division or posterolateral division of the left coronary artery at a level of 40-70% from the apex was performed 53 +/- 21 days before acute experiments. Shock-induced vulnerability was assessed in infarcted (n = 8) and structurally normal (n = 8) hearts by delivering internal monophasic shocks at different shock strengths and delivery phases. Electrical activities from the anterior epicardium during shock application and during shock-induced arrhythmias were optically recorded and quantitatively analyzed. Ligation resulted in a transmural left ventricular free wall infarction mainly located at the apical region with a consistent endocardial border zone (BZ) as confirmed by histological studies. There were significant increases in the incidence, severity, and duration of shock-induced arrhythmias in the infarcted hearts versus controls due to 1) postshock break-excitation wavefronts that frequently originated near the infarction BZ and 2) the existence of an infarction BZ that created an anatomic reentry pathway and facilitated arrhythmia maintenance. In conclusion, the infarction BZ contributes to both increased shock-induced arrhythmogenesis and arrhythmia maintenance in the rabbit model of healed MI.

Animals↗
PubMed2005

Mechanisms of superiority of ascending ramp waveforms: new insights into mechanisms of shock-induced vulnerability and defibrillation.

Monophasic ascending ramp (AR) and descending ramp (DR) waveforms are known to have significantly different defibrillation thresholds. We hypothesized that this difference arises due to differences in mechanisms of arrhythmia induction for the two waveforms. Rabbit hearts (n = 10) were Langendorff perfused, and AR and DR waveforms (7, 20, and 40 ms) were randomly delivered from two line electrodes placed 10 mm apart on the anterior ventricular epicardium. We optically mapped cellular responses to shocks of various strengths (5, 10, and 20 V/cm) and coupling intervals (CIs; 120, 180, and 300 ms). Optical mapping revealed that maximum virtual electrode polarization (VEP) was reached at significantly different times for AR and DR of the same duration (P < 0.05) for all tested CIs. As a result, VEP for AR were stronger than for DR at the end of the shock. Postshock break excitation resulting from AR generated faster propagation and typically could not form reentry. In contrast, partially dissipated VEP resulting from DR generated slower propagation; the wavefront was able to propagate into deexcited tissue and thus formed a shock-induced reentry circuit. Therefore, for the same delivered energy, AR was less proarrhythmic compared with DR. An active bidomain model was used to confirm the electrophysiological results. The VEP hypothesis explains differences in vulnerability associated with monophasic AR and DR waveforms and, by extension, the superior defibrillation efficacy of the AR waveform compared with the DR waveform.

Animals↗
PubMed2005

Fluorescence imaging for real-time monitoring of high-intensity focused ultrasound cardiac ablation.

Side effects and limitations of radio-frequency ablation of cardiac arrhythmias prompted search for alternative energy sources and means of their application. High-intensity focused ultrasound (HIFU) is becoming an increasingly attractive modality for ablation because of its unique ability for non-invasive or minimally invasive, non-contact focal ablation in 3D volume without affecting intervening and surrounding cells. The purpose of this study is to develop a real-time monitoring technique to elucidate HIFU-induced modifications of electrical conduction in cardiac tissues and to investigate the HIFU cardiac ablation process to help to achieve optimal HIFU ablation outcome. We conducted experimental studies applying HIFU at 4.23 MHz to ablate the atrio-ventricular (AV) node and ventricular tissue of Langendorff-perfused rabbit hearts. We employed fluorescent voltage-sensitive dye imaging and surface electrodes to monitor the electrical conduction activity induced by HIFU application in real time. In ventricular epicardium HIFU ablation, fluorescent imaging revealed gradual reduction of the plateau phase and amplitude of the action potential. Subsequently, conduction block and cell death were observed at the site of ablation. When HIFU was applied to the AV node, fluorescent imaging and electrograms revealed the development of the AV block. The study establishes that real-time fluorescent imaging provides novel monitoring and assessment to study HIFU cardiac ablation, which may be able to provide improved understanding of HIFU cardiac ablation process and mechanism useful for development of successful clinical applications.

Animals↗
PubMed2005

Electroporation of the heart.

Defibrillation shocks are commonly used to terminate life-threatening arrhythmias. According to the excitation theory of defibrillation, such shocks are aimed at depolarizing the membranes of most cardiac cells resulting in resynchronization of electrical activity in the heart. If shock-induced changes in transmembrane potential are large enough, they can cause transient tissue damage due to electroporation. In this review evidence is presented that (a) electroporation of the heart tissue can occur during clinically relevant intensities of the external electrical field, and (b) electroporation can affect the outcome of defibrillation therapy; being both pro- and anti-arrhythmic.

Animals↗
PubMed2005

Hibernator Citellus undulatus maintains safe cardiac conduction and is protected against tachyarrhythmias during extreme hypothermia: possible role of Cx43 and Cx45 up-regulation.

BACKGROUND: Most mammals experience cardiac arrest during hypothermia. In contrast, hibernators remain in sinus rhythm even at body temperatures of 0 degrees C. OBJECTIVES: The purpose of this study was to quantify electrical activity and connexin expression in the heart of hibernating Siberian ground squirrel Citellus undulatus. METHODS: Optical imaging and microelectrode recordings were conducted in Langendorff-perfused hearts and isolated papillary muscles of summer active (SA, n = 19), winter hibernating (WH, n = 21), interbout arousal (IBA, n = 12), and winter active (WA, n = 3) ground squirrels and rabbits (n = 14) at temperatures from +37 degrees C to +3 degrees C. RESULTS: All studied SA and WH hearts maintained spontaneous sinus rhythm, safe propagation through the entire conduction system, and normal pattern of ventricular excitation at all temperatures. However, three of the seven IBA and all rabbit hearts lost excitability at 10 degrees C +/- 1 degrees C and 12 degrees C +/- 1 degrees C, respectively. In WH, SA, and IBA ground squirrels, temperature reduction from 37 degrees C to 3 degrees C resulted in a 10-fold slowing of ventricular conduction velocity and increased excitation threshold. At any temperature, WH ventricles had faster conduction velocity and lower excitation threshold compared with SA and IBA. Immunolabeling demonstrated that connexin43 (Cx43) was significantly up-regulated in WH and WA compared with SA myocardium: Cx43 area density was 12.4 +/- 1.3, 15.0 +/- 3.0 and 8.6 +/- 1.1 microm(2)/1,000 microm(2), respectively. Moreover, Cx45 was expressed in the WH but not in the SA or WA ventricles. CONCLUSION: Hibernator Citellus undulatus has evolved to maintain safe conduction at extreme hypothermia via up-regulation of Cx43 and Cx45 in order to protect the heart against arrhythmia associated with hypothermia.

Animals↗
PubMed2005

Optical mapping of the atrioventricular junction.

In the normal heart, the atrioventricular node (AVN) is part of the sole pathway between the atria and ventricles, and is responsible for the appropriate atrial-ventricular delay. Under normal physiological conditions, the AVN controls appropriate frequency-dependent delay of contractions. The AVN also plays an important role in pathology: it protects ventricles during atrial tachyarrhythmia, and during sinoatrial node failure the atrioventricular (AV) junction assumes the role of pacemaker. Finally, the AV junction provides an anatomic substrate for AV nodal reentrant tachycardia, which is the most prevalent supraventricular tachycardia in humans. Using fluorescent imaging with voltage-sensitive dye and immunohistochemistry, we have investigated the structure-function relationship of the atrioventricular (AV) junction during normal conduction, reentry, and junctional rhythm. We identified the site of origin of junctional rhythm at the posterior extension of the AV node (AVN) in 78% (n=23) of the studied hearts and we found that this pacemaker is sensitive to autonomic control. For instance, when the autonomic nervous system was activated using subthreshold stimulation, a transient accelerated junctional rhythm was observed when subthreshold stimulation was terminated. A very similar phenomenon is observed clinically during slow pathway ablations treating AV nodal reentrant tachycardia (AVNRT). The autonomic control of the AV junction was investigated using immunohistochemistry, showing that the AV junction of the rabbit is very densely innervated with both cholinergic and adrenergic neurons. The posterior AV nodal extension was similar to the compact AVN as determined by morphologic and molecular investigations. In particular, both the posterior extension and the compact node express the pacemaking channel HCN4 (responsible for the IF current) and neurofilament 160. In the rabbit heart, AV junction conduction, reentrant arrhythmia, and spontaneous rhythm are governed by heterogeneity of expression of several isoforms of gap junctions and ion channels, and these properties are regulated by the autonomic nervous system. Uniform neurofilament expression suggests that AV nodal posterior extensions are an integral part of the cardiac pacemaking and conduction system.

Action Potentials↗
PubMed2005

The Gurvich waveform has lower defibrillation threshold than the rectilinear waveform and the truncated exponential waveform in the rabbit heart.

Implantable cardioverter defibrillator studies have established the superiority of biphasic waveforms over monophasic waveforms. However, external defibrillator studies of biphasic waveforms are not as widespread. Our objective was to compare the defibrillation efficacy of clinically used biphasic waveforms, i.e., truncated exponential, rectilinear, and quasi-sinusoidal (Gurvich) waveforms in a fibrillating heart model. Langendorff-perfused rabbit hearts (n = 10) were stained with a voltage-sensitive fluorescent dye, Di-4-ANEPPS. Transmembrane action potentials were optically mapped from the anterior epicardium. We found that the Gurvich waveform was significantly superior (p < 0.05) to the rectilinear and truncated exponential waveforms. The defibrillation thresholds (mean +/- SE) were as follows: Gurvich, 0.25 +/- 0.01 J; rectilinear-1, 0.34 +/- 0.01 J; rectilinear-2, 0.33 +/- 0.01 J; and truncated exponential, 0.32 +/- 0.02 J. Using optically recorded transmembrane responses, we determined the shock-response transfer function, which allowed us to predict the cellular response to waveforms at high accuracy. The passive parallel resistor-capacitor model (RC-model) predicted polarization superiority of the Gurvich waveform in the myocardium with a membrane time constant (taum) of less than 2 ms. The finding of a lower defibrillation threshold with the Gurvich waveform in an in vitro model of external defibrillation suggests that the Gurvich waveform may be important for future external defibrillator designs.

Action Potentials↗